Alzheimer's disease is the most common neurodegenerative disorder and is characterized clinically by cognitive dysfunction and pathologically by the formation of extracellular amyloid plaques and intraneuronal deposition of aggregated tau into neurofibrillary tangles. Aging is arguably the most important risk factor predisposing to the development of Alzheimer's disease and significant evidence implicates protein homeostasis, or proteostasis, failure as a key mechanism underlying age-related disease risk. However, the mechanistic basis for impaired proteostasis with advancing age remains incompletely understood. Recently work in model organisms has demonstrated cross talk between peripheral tissue proteostasis and misfolding and abnormal aggregation of proteins in the central nervous system, but the molecular and cellular mechanisms contributing to tissue-level proteostasis regulation are largely unknown. Here we capitalize on a recent unbiased forward genetic screen in Drosophila, which implicated multiple novel cellular pathways in age-related proteostasis failure and neurodegeneration. We have further determined that a number of novel proteostasis identified in the screen act in a non-cell autonomous fashion to regulate brain proteostasis. Based on these results we will expand our studies to define, using powerful model organism genetics, the range of pathways in peripheral tissues capable of altering brain proteostasis. We will further determine if peripheral manipulation of proteostasis through genetic manipulation of these pathways influences neurodegeneration in experimentally tractable Drosophila models related to Alzheimer's disease, namely tau and A transgenic flies. Finally, we will analyze tissue from aging mice, as well as from Alzheimer's disease patients and controls, to ensure that the insights we develop from our powerful, but simple, model organism are relevant to the disease itself. These studies will ultimately expand the array of molecular and cellular targets available for therapy development in Alzheimer's disease and related disorders.